Cannot Target What Cannot Be Seen: Molecular Imaging of Cancer Stem Cells
Abstract
:1. The Necessity for Research into the Imaging of Cancer Stem Cells
2. The Multiple Facets of Cancer Stem Cells and Their Role in Tumour Development and Progression
Experiment-Based Properties of Cancer Stem Cells | References | |
---|---|---|
Cellular and cell cycle-related properties | Long-lived (immortal) | [11] |
Can create all heterogeneous lineages of the original tumour | [6] | |
Able to divide by symmetrical division | [26] | |
Commonly dwell in microenvironmental niches within the tumour | [35] | |
Undergo cell recruitment (from their niche into the mitotic cycle) | [2] | |
Can present both a stationary state (quiescent) as well as a migratory state (invasive) | [21] | |
Have different phenotypes that dictate their cellular behaviour | [36] | |
Radiobiological and treatment-related properties | Exhibit enhanced DNA repair compared to their non-stem counterparts | [11] |
Demonstrate higher treatment resistance than non-stem cancer cells | [11] | |
Capable of tumour repopulation during treatment | [37] | |
Can induce shortening of cell cycle duration in response to cell loss | [20,38] | |
Undergo drastic changes in perivascular niches triggering bouts of hypoxia and reoxygenation | [15] | |
Characterised by cellular plasticity (dynamic transformation from CSC into non-stem cancer cell and vice versa) | [39] | |
Display altered cellular kinetics during fractionated radiotherapy | [40,41] | |
Evade the immune response | [10] |
3. Current Biomarkers Specific for Cancer Stem Cells
CSC Marker | Cancer Site | References |
---|---|---|
CD133+ | lung, pancreatic, colon, prostate, brain, liver | [50,68] |
ABCG2high | lung cancer | [69,70] |
CD44+ | pancreas, colon, prostate, head and neck | [71,72,73,74] |
EpCAM+ | pancreas, colon, liver | [60,75] |
CD24+ | pancreas, colon | [71] |
CD138− | multiple myeloma | [76] |
CD166+ | colon | [77] |
CD90+ | brain | |
CD49f+ | brain | |
CD38 | lung | [78] |
CD90-CD117 | leukemia | [78] |
CD19 | ALL, NHL, MCL | |
EGRF | glioblastoma, breast, and lung cancers, as well as renal, pancreatic, ovarian, and head and neck cancers | [79] |
Integrins | lung, prostate, colon, glioblastoma, pancreas, breast | [80] |
Keratin 19 | hepatocellular carcinoma | [64] |
4. In Vivo Molecular Imaging of Cancer Stem Cells
Molecular Imaging | Cell Line | Imaging Agent | CSC Biomarker | Type | Reference |
---|---|---|---|---|---|
MRI | Liver | HEA125@magnetic iron microbeads | EpCAM | Mice | [106] |
MRI | Human breast | FDH heavy chain | CD44+/CD24− | Mice | [107] |
MRI | Neuroblastoma | LV@Tet@FDH | Iron | Mice | [108] |
MRI | C6 Glioma | PEG3@LV@FDH | Iron | Mice | [109] |
MRI | Human breast | Apoferittin | Iron | Mice | [110] |
MRI | Human breast | APTEDB@SPION | EDB-FN | Mice | [111] |
MRI | Human breast | Dox@APTEDB@SPION | EDB-FN | Mice | [112] |
Dual MRI | Pancreas | Fe3O4@PMn NPs | HIF-1α aptamer | Mice | [113] |
MRI | Human breast | SWCN + SPION | CD44 | Murine | [92] |
SPECT | Human breast | 67Ga | CD44 | Murine | [92] |
MRI | Human and murine breast | Fe3O4@PPr@HA + DAPT | CD44 | Mice | [116] |
MRI | Human colon | ASCT2 | CD44, CD166 | Mice | [114] |
PET | Mice colon | 64Cu-ATSM | CD133 | Mice | [117,118] |
PET | Human CT26 colon | 125I-ANC9C5 | CD133 | Mice | [119] |
PET | Mice CT26 colon | 125I-NIS | CD133 | Mice | [120] |
PET | Human glioma U251 and GBM NCH421k | 64Cu-NOTA-AC133 mAb | CD133 | Mice | [68] |
PET | Human GBM U87MG | 64Cu-NOTA-YY146 | CD146 | Mice | [121] |
SPECT | Human GBM U87MG | 111I- MSN-DOTA | - | Mice | [122] |
PET | TNBC | 89Zr@CS-GA-MLP | CD44 | Mice | [123] |
PET | Human breast | 18F-FDG | CSC metabolic phenotype | Human retrospective study | [124] |
SPECT/NIR | Human colon HCT116 | 99Tc-TEx-Cy7 | - | Mice | [125] |
PET/MRI | MSC | 18F- Fe3O4@Al(OH)3 | - | Mice | [126] |
Imaging of Circulating Tumour Cells
5. Challenges and Future Prospects
- Biological/treatment-related issues:
- (a)
- To identify and characterise the various CSC phenotypes for a more personalised approach and patient stratification.
- (b)
- To elucidate the role of quiescent CSCs in tumour progression and dissemination; should they be targeted in their dormant phase or triggered into the cell cycle?
- (c)
- To obstruct DNA repair pathways in CSCs to improve cellular radiosensitisation.
- (d)
- To identify the need for interference with cellular plasticity and its pathways for keeping the CSC subpopulation to a minimum.
- (e)
- To clarify the role and the need for cell-differentiating agents in tumour sensitisation.
- (f)
- To further investigate the impact of fractionated radiotherapy on CSC dynamics.
- CSC identification/marker-related issues:
- (a)
- To develop tumour-specific CSC markers with high specificity for in vivo imaging.
- (b)
- To reliably quantify the in vivo CSC population based on specific markers.
- (c)
- To identify phenotype-specific CSCs in view of the differential response to therapy.
- (d)
- To clinically evaluate other than through cell surface markers (which are not always uniformly useful in identifying CSCs) for a more reliable patient stratification.
- (e)
- To identify and employ markers that interconnect with the physiological function of CSCs, providing more accurate detection.
- In vivo imaging-related issues:
- (a)
- To perfect in vivo imaging of endogenous CSCs. Although single-cell resolution MRI imaging has been reported for small animals in exogenous models, in vivo imaging of endogenous CSCs at the cell level is still a developing area.
- (b)
- To develop high sensitivity and specificity of MRI- and PET-compatible agents that target CSCs. Advances in technology and radiotracer fabrications, along with high functional and molecular sensitivity, have made PET’s potential equal to MRI.
- (c)
- To develop hybrid imaging techniques for CSCs. Combined modalities have shown promise, although not yet at the proof-of-principle capacity, to overcome several limitations of individual modes.
- (d)
- To encourage the translation of in vivo CSC imaging from animal studies to humans. The number of human studies on the functional imaging of CSCs is still scarce.
- (e)
- To improve the detection resolution of non-invasive modalities at the cellular level. Currently, in vivo imaging is able to identify regions/clusters containing CSCs; nevertheless, the translation of CSC biology to clinical application relies on the identification of individual CSCs due to their scarcity.
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Marcu, L.G.; Moghaddasi, L.; Bezak, E. Cannot Target What Cannot Be Seen: Molecular Imaging of Cancer Stem Cells. Int. J. Mol. Sci. 2023, 24, 1524. https://doi.org/10.3390/ijms24021524
Marcu LG, Moghaddasi L, Bezak E. Cannot Target What Cannot Be Seen: Molecular Imaging of Cancer Stem Cells. International Journal of Molecular Sciences. 2023; 24(2):1524. https://doi.org/10.3390/ijms24021524
Chicago/Turabian StyleMarcu, Loredana G., Leyla Moghaddasi, and Eva Bezak. 2023. "Cannot Target What Cannot Be Seen: Molecular Imaging of Cancer Stem Cells" International Journal of Molecular Sciences 24, no. 2: 1524. https://doi.org/10.3390/ijms24021524